Sustainable and efficient skin absorption behaviour of transdermal drug: The effect of the release kinetics of permeation enhancer

At present, how the release kinetics of permeation enhancers affected their enhancement efficacy on drug skin absorption and its molecular mechanisms remained unclear. Herein, the release kinetics of permeation enhancer (Plurol Oleique CC (POCC)) which involved release percent (PR), release duration (RD) and release kinetic constant (k) and its enhancement efficacy on drug skin absorption were investigated with in vitro skin retention study and in vitro skin permeation study, respectively. POCC released from the acidic-drug loading patches followed with the Higuchi release model and had short RD (8-16 h), resulting in its unsustainable enhancement efficiency for acidic drugs. However, POCC released from the basic-drug loading patches followed with zero-order model with long RD (12-24 h), inducing a sustainable and efficient enhancement efficiency for basic drugs. The lower variance of an innovative parameter permeation enhancement coefficient (CPE) represented the relatively sustainable and effective enhancement effect and was listed as followed: 0.20 (Zaltoprofen (ZPF)), 0.31 (Diclofenac (DCF)), 0.27 (Indomethacin (IMC)), 0.07 (Azasetron (AST)), 0.11 (Oxybutynin (OBN)) and 0.06 (Donepezil (DNP)). According to the results of FT-IR, MTDSC, 13C NMR spectra, molecular dynamics simulation, SAXS and Raman imaging, the Higuchi release model was caused by strong interaction between the acid drugs and pressure sensitive adhesive (PSA). This strong interaction induced faster diffusion speed of POCC from acidic-drug loading patches and make the swell degree of long periodicity phase (LPP) of stratum corneum (SC) lipids reached plateau early. The zero-order release model was because the weak interaction between basic drugs and PSA making most of POCC was still bound to PSA, which in turn lead to LPP swelled at a slow but sustainable process. In conclusion, zero-order release kinetic of POCC lead to sustainable and efficient penetration enhancement efficiency on basic drug, while the Higuchi release kinetic showed opposite effect for acidic drugs. A deep understanding of release kinetics of enhancer and its enhancement efficiency may drive the ideal selection of permeation enhancers and rational optimization of transdermal patches.